FDA has responded to requests included in two reports accompanying the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (Public Law No. 111-80) – House Report No. 111-279 and Senate Report 111-39 – requesting information from FDA on generic Anti-Epileptic Drugs (“AEDs”), and in particular, whether there are increased risks to patients who are switched from a brand-name AED to an approved, bioequivalent generic version. FDA concludes in the Agency’s 9-page report recently submitted to Congress that small analyses conducted by FDA do not show that generic AEDs are less effective than their brand-name counterparts, but that further study is necessary.

We initially reported on the Congressional requests in November 2009, and have been closely following the issue. In November 2010, we reported that FDA responded to a request from New Jersey State Senator Joseph F. Vitale (D) concerning legislation that would require pharmacists in New Jersey to dispense epilepsy drugs from the same manufacturer as previously dispensed for certain patients, unless otherwise prescribed, and noted that FDA’s response seemed to give some foreshadowing as to what conclusions the Agency would include in its report to Congress. That appears to be the case.

The report to Congress notes that:

Several small analyses conducted by FDA using data available in its Adverse Event Reporting System (AERS) do not provide evidence that generic anti-epileptic drug products are less effective than brand name products. However, it is difficult to draw reliable conclusions about therapeutic equivalence from the AERS data because the adverse event reports are not necessarily representative of a random sampling of the patient population, nor can they be corrected for the relative market share of the various brand and generic products to determine if there is actually a difference in the incidence of adverse events for generic products.

In particular, FDA analyzed post-marketing surveillance reports of two AEDs for which safety and efficacy concerns were reportedly raised by stakeholders – Levetiracetam and Lamotrigine – for evidence of therapeutic inequivalence. Based on FDA’s analyses, the Agency notes that the so-called “Weber effect” – a phenomenon that states that the number of reported adverse reactions for a drug increases until about the middle to the end of the second year of marketing – is likely “a factor contributing to increased patient complaints following switches from brand name to newly-approved generic anti-epileptic drugs.” In addition, FDA says that “it is possible that the wide publicity given to negative literature about generic anti-epileptic drugs, much of which is disseminated by various epilepsy societies, may influence patients that recently switched to generics.” Thus, according to FDA, “background breakthrough seizure and adverse event rates may be comparable whether the same patient is being treated with a generic drug or the brand drug, but because of the generic switch, the patient may be more likely to complain of adverse events and breakthrough seizures.”

To better evaluate differences between brand and generic AEDs, FDA says in the report that some studies are in the works, including a study by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke intended to determine whether some epilepsy patients respond differently to AEDs from different manufacturers, and a similar study designed by the Office of generic Drugs that will be performed under FDA’s Critical Path Program and that is intended “to evaluate bioequivalence of an ‘older’ generic AED, such as carbamazepine, and a ‘newer’ generic AED, such as zonisamide, versus their respective reference products.”

With respect to AED bioequivalence testing, FDA states that the Agency “is currently exploring the pros and cons of narrowing the acceptance criteria for the 90 percent confidence interval for AUC for certain drugs.” In April 2010, FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee held a meeting and discussed, among other things, tightening bioequivalence standards (e.g., from the current 80%-125% standard to 90%-111%) for drugs whose dosing must be carefully adjusted to avoid adverse events, including Narrow Therapeutic Index (“NTI”) drugs. Although the advisory committee was supportive of tightening the bioequivalence standards for NTI drugs, FDA’s report to Congress notes that “not all anti-epileptic drugs are considered NTI drugs based on their efficacy and toxicity profiles. Therefore, other selection criteria would need to be established as a basis for changing the current bioequivalence standards for the AEDs.”